scholarly journals Griffithsin and Carrageenan Combination Results in Antiviral Synergy against SARS-CoV-1 and 2 in a Pseudoviral Model

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 418
Author(s):  
Sahar Alsaidi ◽  
Nadjet Cornejal ◽  
Oneil Mahoney ◽  
Claudia Melo ◽  
Neeharika Verma ◽  
...  
Keyword(s):  
Combination Index ◽  
Antiviral Agents ◽  
Therapeutic Index ◽  
Antagonistic Effect ◽  
Sulfated Polysaccharides ◽  
Synergistic Activity ◽  
Species Barrier ◽  
Half Maximal Effective Concentration ◽  
A Cell ◽  
Inhibition Analysis

Over 182 million confirmed cases of COVID-19 and more than 4 million deaths have been reported to date around the world. It is essential to identify broad-spectrum antiviral agents that may prevent or treat infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but also by other coronaviruses that may jump the species barrier in the future. We evaluated the antiviral selectivity of griffithsin and sulfated and non-sulfated polysaccharides against SARS-CoV-1 and SARS-CoV-2 using a cytotoxicity assay and a cell-based pseudoviral model. The half-maximal cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were determined for each compound, using a dose-response-inhibition analysis on GraphPad Prism v9.0.2 software (San Diego, CA, USA). The therapeutic index (TI = CC50/EC50) was calculated for each compound. The potential synergistic, additive, or antagonistic effect of different compound combinations was determined by CalcuSyn v1 software (Biosoft, Cambridge, UK), which estimated the combination index (CI) values. Iota and lambda carrageenan showed the most potent antiviral activity (EC50 between 3.2 and 7.5 µg/mL). Carrageenan and griffithsin combinations exhibited synergistic activity (EC50 between 0.2 and 3.8 µg/mL; combination index <1), including against recent SARS-CoV-2 mutations. The griffithsin and carrageenan combination is a promising candidate to prevent or treat infections by SARS-CoV-1 and SARS-CoV-2.

scholarly journals Human Coronaviruses: Counteracting the Damage by Storm

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1457
Author(s):  
Dewald Schoeman ◽  
Burtram C. Fielding
Keyword(s):  
Immune Response ◽  
Severe Disease ◽  
Antiviral Agents ◽  
The Elderly ◽  
Highly Pathogenic ◽  
Vaccine Responses ◽  
Cell Mediated Immune Response ◽  
Inhibition Antibody ◽  
A Cell ◽  
Human Coronaviruses

Over the past 18 years, three highly pathogenic human (h) coronaviruses (CoVs) have caused severe outbreaks, the most recent causative agent, SARS-CoV-2, being the first to cause a pandemic. Although much progress has been made since the COVID-19 pandemic started, much about SARS-CoV-2 and its disease, COVID-19, is still poorly understood. The highly pathogenic hCoVs differ in some respects, but also share some similarities in clinical presentation, the risk factors associated with severe disease, and the characteristic immunopathology associated with the progression to severe disease. This review aims to highlight these overlapping aspects of the highly pathogenic hCoVs—SARS-CoV, MERS-CoV, and SARS-CoV-2—briefly discussing the importance of an appropriately regulated immune response; how the immune response to these highly pathogenic hCoVs might be dysregulated through interferon (IFN) inhibition, antibody-dependent enhancement (ADE), and long non-coding RNA (lncRNA); and how these could link to the ensuing cytokine storm. The treatment approaches to highly pathogenic hCoV infections are discussed and it is suggested that a greater focus be placed on T-cell vaccines that elicit a cell-mediated immune response, using rapamycin as a potential agent to improve vaccine responses in the elderly and obese, and the potential of stapled peptides as antiviral agents.

scholarly journals Identification of Hepatitis C Virus NS5A Inhibitors

2009 ◽  
Vol 84 (1) ◽  
pp. 482-491 ◽  
Author(s):  
Julie A. Lemm ◽  
Donald O'Boyle ◽  
Mengping Liu ◽  
Peter T. Nower ◽  
Richard Colonno ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Therapeutic Index ◽  
Dna Viruses ◽  
Genotype 1A ◽  
A Cell ◽  
Ns3 Protease ◽  
Derivatives Of ◽  
Rna And Dna

ABSTRACT Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that resulted in a 50% inhibition of HCV replicon replication was ∼5 nM, with a therapeutic index of >10,000. The compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93 (Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that, consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A, but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors, as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects on HCV-infected subjects.

scholarly journals Identification and Evaluation of Potential SARS-CoV-2 Antiviral Agents Targeting mRNA Cap Guanine N7-Methyltransferase

2021 ◽  
Author(s):  
Renata Kasprzyk ◽  
Tomasz J. Spiewla ◽  
miroslaw smietanski ◽  
Sebastian Golojuch ◽  
Laura Vangeel ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Therapeutic Interventions ◽  
Binding Assays ◽  
Inhibitory Effects ◽  
Dot Blot ◽  
Rp Hplc ◽  
Structure Activity ◽  
Mrna Capping ◽  
New Ideas ◽  
A Cell

SARS-CoV-2, the cause of the currently ongoing COVID-19 pandemic, encodes its own mRNA capping machinery. Insights into this capping system may provide new ideas for therapeutic interventions and drug discovery. In this work, we employ a previously developed Py-FLINT screening approach to study the inhibitory effects of compounds against the cap guanine N7-methyltransferase enzyme, which is involved in SARS-CoV-2 mRNA capping. We screened five commercially available libraries (7039 compounds in total) to identify 83 inhibitors with IC50 < 50 μM, which were further validated using RP HPLC and dot blot assays. Novel fluorescence anisotropy binding assays were developed to examine the targeted binding site. The inhibitor structures were analyzed for structure-activity relationships in order to define common structural patterns. Finally, the most potent inhibitors were tested for antiviral activity on SARS-CoV-2 in a cell based assay<br>

The in vitro antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with mefloquine/artesunate

2014 ◽  
Vol 60 (1) ◽  
Author(s):  
Wanna Chaijaroenkul ◽  
Kesara Na-Bangchang
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Drug Concentration ◽  
Combination Index ◽  
Antimalarial Drugs ◽  
Antagonistic Effect ◽  
Parasite Growth ◽  
Major Health Problem ◽  
Major Health

AbstractMultidrug resistance Plasmodium falciparum is the major health problem in Thailand. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate the antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with the standard antimalarial drugs mefloquine and artesunate in chloroquine sensitive (3D7) and chloroquine resistant (K1) P. falciparum clones in vitro. Median (range) IC50 (drug concentration which produces 50% parasite growth inhibition) values of the 9-hydroxycalabaxanthone, α-mangostin, artesunate and mefloquine for 3D7 vs K1 clones were 1.5 (0.9-2.1) vs 1.2 (1.1-1.6) μM, 17.9 (15.7.0-20.0) vs 9.7 (6.0-14.0) μM, 1.0 (0.4-3.0) vs 1.7 (1.0-2.5) nM, and 13.3 (11.1-13.3) vs 7.1 (6.7-12.2) nM, respectively. Analysis of isobologram and combination index (CI) of 9-hydroxycalabaxanthone with artesunate or mefloquine showed synergistic and indifference antimalarial interaction, respectively. α-mangostin-artesunate combination exhibited a slight antagonistic effect of antimalarial interaction, whereas α-mangostin and mefloquine combination showed indifference interaction in both clones. The combination of 9-hydroxycalabaxanthone with α-mangostin showed the synergistic antimalarial interaction in both clones

scholarly journals Synergy of Linezolid with Several Antimicrobial Agents against Linezolid-Methicillin-Resistant Staphylococcal Strains

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 496
Author(s):  
María-José Valderrama ◽  
María Alfaro ◽  
Icíar Rodríguez-Avial ◽  
Elvira Baos ◽  
Carmen Rodríguez-Avial ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
Ribosomal Subunit ◽  
Antagonistic Effect ◽  
Prolonged Treatment ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Resistant Strains ◽  
Time Kill ◽  
Selection Of

Linezolid is a synthetic oxazolydinone active against multi-resistant Gram-positive cocci that inhibits proteins synthesis by interacting with the 50S ribosomal subunit. Although linezolid-resistant strains are infrequent, several outbreaks have been recently described, associated with prolonged treatment with the antibiotic. As an alternative to monotherapy, the combination of different antibiotics is a commonly used option to prevent the selection of resistant strains. In this work, we evaluated combinations of linezolid with classic and new aminoglycosides (amikacin, gentamicin and plazomicin), carbapenems (doripenem, imipenem and meropenem) and fosfomycin on several linezolid- and methicillin-resistant strains of Staphylococcus aureus and S. epidermidis, isolated in a hospital intensive care unit in Madrid, Spain. Using checkerboard and time-kill assays, interesting synergistic effects were encountered for the combination of linezolid with imipenem in all the staphylococcal strains, and for linezolid–doripenem in S.epidermidis isolates. The combination of plazomicin seemed to also have a good synergistic or partially synergistic activity against most of the isolates. None of the combinations assayed showed an antagonistic effect.

In Vitro Biological Activity of Adriamycin

1970 ◽  
Vol 56 (3) ◽  
pp. 137-148 ◽  
Author(s):  
Rosella Silvestrini ◽  
Carmela Gambarucci ◽  
Teresa Dasdia
Keyword(s):  
Biological Activity ◽  
Cellular Proliferation ◽  
Therapeutic Index ◽  
Dna And Rna ◽  
Total Inhibition ◽  
A Cell ◽  
Nuclear Structures ◽  
Higher Doses

Adriamycin is an antibiotic, isolated from cultures of a mutant of Streptomyces peucetius, var. caesius, with a chemical structure very similar to daunomycin but with a higher therapeutic index in experimental tumors. The biological activity of this antibiotic has been studied in vitro on the HeLa cell strain. Adriamycin quickly penetrates into the cells and fixes to the nuclear structures with a marked localization at the level of the perinucleolar chromatin. It causes a marked and immediate disturbance of the mitotic process, viz. pre-prophasic inhibition at the low doses and mitotic block at the higher doses. Even the synthesis of DNA and RNA, evaluated autoradiographically as incorporation of 3H-thymidine and 3H-uridine, appear markedly inhibited. The viability of the cells, tested both as regards capacity to give rise to colonies and as regards proliferative activity of a cell population, was seriously reduced, in a degree proportional to the period of treatment and to the concentration of the antibiotic, until total inhibition. In comparison with daunomycin, adriamycin exerts an immediate antimitotic and anti-metabolic effect which, at equivalent doses, is slightly lower than that of daunomycin. The long-term antiproliferative activity on cellular proliferation is however, identical for the two antibiotics.

Rational for targeted polytherapy in sarcoma: Get the genie out of the bottle.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13519-e13519
Author(s):  
Sarah N. Dumont ◽  
Dan Yang ◽  
Amaury Gerard Dumont ◽  
Jean-Yves Blay ◽  
Jonathan C. Trent
Keyword(s):  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Combination Index ◽  
Annexin V ◽  
Hsp90 Inhibitor ◽  
Antagonistic Effect ◽  
Flow Cytometry Analysis ◽  
Combination Therapies ◽  
Undifferentiated Sarcoma ◽  
Luminescent Assay

e13519 Background: While a change of paradigm occurred in the last decade from chemotherapy to targeted therapy for cancer treatment, this work investigates the optimal combination of targeted agents with doxorubicin in sarcoma. Methods: Three sarcoma cell lines were studied RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma) and exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (Hsp90 inhibitor), abacavir (anti-telomerase) and sorafenib (tyrosine kinase inhibitor) alone, combined 2 by 2, then with doxorubicin. Viability was assessed by MTS assay. The Chou and Talalay combination index (CI) was used to determine additive (CI=1), synergistic (CI<1) or antagonistic effect (CI>1). Cell cycle analysis, measure of apoptosis by Annexin V and caspase 3/7 activity were studied using flow cytometry analysis and luminescent assay. Results: In monotherapy, the agents showed 30% to 90% decrease in viability but abacavir, which remained less active. Combination therapies with vorinostat, sorafenib and 17-DMAG showed strong synergism. Abacavir was found antagonistic with each drug. Either vorinostat or 17DMAG synergized with doxorubicin, achieving 60% cell killing compared to doxorubicin alone 12% (p=0.007). However, no synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17DMAG and Doxorubicin did not show synergism but transiently increased the subG1 population at 24H, 70% compared to 30% in monotherapy with an increase in early caspase-independent apoptosis (11% to 36%, p= 0.0008). Conclusions: This work provides evidence of synergism of dual combinations of vorinostat, 17DMAG and sorafenib. In adjunction to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations. [Table: see text]

P.179 A cell-based assay for evaluating potential antiviral agents against HCV

2006 ◽  
Vol 36 ◽  
pp. S116
Author(s):  
S. Aviel ◽  
J. Ben-Porath ◽  
E. Mishori ◽  
D. Slama ◽  
N. Cohen ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
A Cell

Efficacy of Commercial Natural Antimicrobials Alone and in Combinations against Pathogenic and Spoilage Microorganisms

2014 ◽  
Vol 77 (2) ◽  
pp. 269-275 ◽  
Author(s):  
CHAYAPA TECHATHUVANAN ◽  
FATIMA REYES ◽  
JAIRUS R. D. DAVID ◽  
P. MICHAEL DAVIDSON
Keyword(s):  
Shelf Life ◽  
Foodborne Pathogens ◽  
Salmonella Enteritidis ◽  
Microbial Control ◽  
Antagonistic Effect ◽  
Synergistic Activity ◽  
Natural Antimicrobials ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Spoilage Microorganisms

Microbial control strategies are needed in the food industry to prevent foodborne illnesses and outbreaks and prolong product shelf life. The aim of this study was to investigate and compare the efficacy of the commercial natural antimicrobials white mustard essential oil (WMEO), citrus flavonoid and acid blend (CFAB), olive extract (OE), Nisaplin (a compound containing nisin), and lauric arginate (LAE) alone and in combinations against foodborne pathogens and spoilage microorganisms. MICs of individual and combined antimicrobials against Escherichia coli, Salmonella Enteritidis, Enterobacter aerogenes, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus were determined at pH 6.0 and 25°C. WMEO was most effective against B. cereus and S. aureus, with MICs of 250 and 500 mg/liter, respectively. CFAB inhibited all tested microorganisms, requiring only 12 to 35 mg/liter for gram-positive bacteria. For OE, 2,000 mg/liter was needed to achieve microbial inhibition. Nisaplin at 400 to 1,200 mg/liter inhibited only gram-positive bacteria. LAE was effective at low concentrations and required only 20 to 50 mg/liter to inhibit all tested microorganisms. When WMEO was combined with other antimicrobials, the effects were usually additive except for WMEO plus Nisaplin and WMEO+OE, which had synergistic activity against L. monocytogenes and Salmonella Enteritidis, respectively. An antagonistic effect was observed for WMEO+CFAB against E. aerogenes. For WMEO+LAE+CFAB, additive antimicrobial effects were noted against all strains tested except S. aureus, where a synergistic effect occurred. These findings suggest that these commercial natural antimicrobials have potential to enhance food safety by inhibiting foodborne pathogens and extending product shelf life.

Diethylstilbestrol and docetaxel: A phase II study in patients with metastatic, androgen independent prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4627-4627
Author(s):  
B. Montgomery ◽  
D. Lin ◽  
C. Ryan ◽  
M. Garzotto ◽  
T. M. Beer
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Index ◽  
Median Number ◽  
Factor V ◽  
Synergistic Activity ◽  
Overall Response ◽  
Bone Scans ◽  
Number Of Cycles ◽  
Dose Modifications ◽  
Androgen Independent

4627 Background: The combination of diethylstilbestrol (DES) and docetaxel has additive to synergistic activity against prostate cancer in preclinical models and DES inhibits expression of taxane resistant tubulin isoforms. The objective of this study is to determine the effects of the combination of DES and docetaxel on PSA, overall response, and toxicity. Methods: Twenty nine patients with metastatic androgen independent prostate cancer progressing by rising PSA or scan were treated with DES 5 mg daily the day prior to docetaxel and 1 mg daily continuously in combination with Docetaxel 36mg/m2 IV weekly for 3 weeks of a 4 week cycle. Prophylactic anticoagulation was used in all patients. All patients were assessed by PSA monthly and CT or bone scans every 3 cycles. Dose modifications for hematologic, hepatic and renal toxicity were made. The RECIST criteria and PSA decline by >50% which was maintained for 4 weeks were used. Results: The median age is 69 years (56–84), SWOG PS 0 (0–1), alkaline phosphatase 120 U/L (45–523), Hgb 12.6 g/dL (9.2–16.3), PSA 67 ng/dL (6–1962). The median number of cycles is 5. The median follow up after completion of therapy is 6 mos (1–18). Soft tissue metastases were present in 46% of patients and bone metastases in 96%. Twenty four patients are evaluable for response and toxicity. Of these, 18 patients (75%) had PSA responses and the PSA declined by >90% in 9 patients (38%). The overall response for was 75%. 11 patients suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid induced ulcer. The median number of cycles for responding patients is 9. Two patients developed thrombosis and were positive for Factor V mutations. Conclusions: The combination of DES and docetaxel is well tolerated and toxicity is indistinguishable from docetaxel alone. The overall response rate was 75%, with approximately half of responding patients achieving a PSA < 4.0, suggesting that DES improves the therapeutic index of docetaxel substantially and is an effective regimen using easily administered drugs. (Supported by Sanofi Aventis). [Table: see text]

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